The present invention pertains to nutritional and pharmaceutical compositions for treating and/or preventing cyclooxygenase-2 mediated diseases and to a process for increasing the cyclooxygenase-2 inhibiting activity of a product. In particular, the present invention also relates to the use of one ore more milk protein fractions and/or one ore more milk protein preparations for inhibiting the activity of cyclooxygenase-2, specifically for the preparation of a food product or a medicament for treating and/or preventing cyclooxygenase-2 mediated diseases.
Cyclooxygenase (COX) enzymes are key enzymes required for the conversion of arachidonic acid to prostaglandins (PGs). Two isoforms of COX have been identified so far, COX-1 and COX-2, which differ in many respects: COX-1 is expressed constitutively in most tissues and is presumed to be responsible for the production of prostaglandins that control normal physiological functions, such as the maintenance of the gastric mucosa and the regulation of renal blood flow. The second isoform, COX-2, does not seem to be constitutively expressed in most of the normal tissues, but is highly inducible and may be found at particular locations only, e.g. at sites of inflammation and in cancer cells.
Although COX-enzymes are found to be membrane-bound, they do not have a conventional trans-membrane region. Instead, they contain four amphipathic helices juxtaposed to form a region of hydrophobicity. This hydrophobic region anchors the “lower” portion of the enzyme in the membrane. The active site of cyclooxygenase is located in the area of hydrophobicity near the amphipathic helices. Substrate and inhibitors of the enzyme are considered to reach the active site via a channel embodied in the lipid bilayer (W. Krause, R. N. Dubois, Prostaglandins & other Lipid Mediators 61 (2000), 145-161).
COX-inhibitors, and in particular COX-2 inhibitors, are used to treat a variety of different diseases, such as inflammatory diseases, and are also used as analgesics. In addition, it has been found that COX-2 is commonly over-expressed in premalignant and malignant tissues and a treatment with COX-2 inhibitors has been shown to reduce the formation of intestinal, esophageal, tongue, breast, skin, lung and bladder tumors in animals (K. Subbaramaiah, A. J. Dannenberg, TRENDS in Pharmacological Sciences 24 (2003), 96-102).
Various well known non-steroidal anti-inflammatory drugs (so called NSAIDs), such as e.g. aspirin and ibuprofen, inhibit COX-1 and COX-2. Recently, a new class of inhibitors (COXIBs) has been described which specifically inhibits the COX-2 enzyme only (M. E. Turini, R. N. Dubois, Physiology And Diseases. Annu. Rev. Med. 53 (2002), 35-57). However, NSAIDs are known to cause serious side-effects, e.g. renal problems and duodenal and stomach ulceration.